European journal of medicinal chemistry

1768-32542502023Mar15European journal of medicinal chemistryEur J Med ChemThioxanthenone-based derivatives as multitarget therapeutic leads for Alzheimer's disease.11516911516910.1016/j.ejmech.2023.115169S0223-5234(23)00084-3A set of twenty-five thioxanthene-9-one and xanthene-9-one derivatives, that were previously shown to inhibit cholinesterases (ChEs) and amyloid β (Aβ₄₀) aggregation, were evaluated for the inhibition of tau protein aggregation. All compounds exhibited a good activity, and eight of them (5-8, 10, 14, 15 and 20) shared comparable low micromolar inhibitory potency versus Aβ₄₀ aggregation and human acetylcholinesterase (AChE), while inhibiting human butyrylcholinesterase (BChE) even at submicromolar concentration. Compound 20 showed outstanding biological data, inhibiting tau protein and Aβ₄₀ aggregation with IC₅₀ = 1.8 and 1.3 μM, respectively. Moreover, at 0.1-10 μM it also exhibited neuroprotective activity against tau toxicity induced by okadoic acid in human neuroblastoma SH-SY5Y cells, that was comparable to that of estradiol and PD38. In preliminary toxicity studies, these interesting results for compound 20 are somewhat conflicting with a narrow safety window. However, compound 10, although endowed with a little lower potency for tau and Aβ aggregation inhibition additionally demonstrated good inhibition of ChEs and rather low cytotoxicity. Compound 4 is also worth of note for its high potency as hBChE inhibitor (IC₅₀ = 7 nM) and for the three order of magnitude selectivity versus hAChE. Molecular modelling studies were performed to explain the different behavior of compounds 4 and 20 towards hBChE. The observed balance of the inhibitory potencies versus the relevant targets indicates the thioxanthene-9-one derivatives as potential MTDLs for AD therapy, provided that the safety window will be improved by further structural variations, currently under investigation.Copyright © 2023 Elsevier Masson SAS. All rights reserved.TonelliMicheleMDepartment of Pharmacy, University of Genoa, 16132, Genoa, Italy. Electronic address: michele.tonelli@unige.it.CattoMarcoMDepartment of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, 70125, Bari, Italy. Electronic address: marco.catto@uniba.it.SabatéRaimonRDepartment of Pharmacy and Pharmaceutical Technology and Physical-Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028, Barcelona, Spain. Electronic address: rsabate@ub.edu.FrancesconiValeriaVDepartment of Pharmacy, University of Genoa, 16132, Genoa, Italy.LauriniErikEMolecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), Department of Engineering and Architecture, University of Trieste, 34127, Trieste, Italy.PriclSabrinaSMolecular Biology and Nanotechnology Laboratory (MolBNL@UniTS), Department of Engineering and Architecture, University of Trieste, 34127, Trieste, Italy; Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236, Lodz, Poland.PisaniLeonardoLDepartment of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, 70125, Bari, Italy.MinieroDaniela ValeriaDVDepartment of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70125, Bari, Italy.LiuzziGrazia MariaGMDepartment of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, 70125, Bari, Italy.GattaElenaEDepartment of Physics, University of Genoa, 16146, Genoa, Italy.ReliniAnnalisaADepartment of Physics, University of Genoa, 16146, Genoa, Italy.GavínRosalinaRInstitute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028, Barcelona, Spain; Institute of Neuroscience, University of Barcelona, 08028, Barcelona, Spain.Del RioJose AntonioJAInstitute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028, Barcelona, Spain; Institute of Neuroscience, University of Barcelona, 08028, Barcelona, Spain.SparatoreFabioFDepartment of Pharmacy, University of Genoa, 16132, Genoa, Italy.CarottiAngeloADepartment of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, 70125, Bari, Italy.engJournal Article20230202